TWI652078B - Blood purification column - Google Patents

Abstract

The object of the present invention is to prevent the activation of blood caused by the air remaining in the pipe string, or to prevent the activation of blood caused by the air remaining in the pipe string, by using the filter sheet contained in the blood purification pipe string to greatly improve the outgassing property mixed into the pipe string. The decrease in the contact area between the adsorbent and the blood reduces the adsorption performance.

The blood purification tube string of the present invention is characterized in that it has an adsorbent body and a sleeve with open ends at both ends. The adsorbent body is housed inside the sleeve, and one end of the two ends of the sleeve is a blood inflow side end. The other end is a blood outflow end, and a filter is arranged on the blood inflow end and / or the blood outflow end of the cannula, and the filter meets the following necessary conditions:

(1) The aperture ratio is 5% or more and 80% or less

(2) The equivalent diameter of the mesh is 1 μm or more and 5000 μm or less

(3) The ratio of the equivalent diameter of the mesh to the average circular equivalent diameter of the voids of the adsorbent is 45% or more.

Description

Blood purification column

The present invention relates to a blood purification pipe string, which is a pipe string used for blood purification and the like, and has excellent gas-exhausting property and does not easily cause blood coagulation in a circuit when blood is introduced.

A treatment method called Apheresis therapy is known, which temporarily extracts the patient's blood outside the body, removes the causative substances in the extracted blood by treatment such as adsorption, filtration, and sends the subsequent blood. Back into the patient. This plasma clearance therapy can be used for the treatment of autotoxic diseases such as drug poisoning, food poisoning, familial hypercholesterolemia, or ulcerative colitis, Crohn's disease, rheumatoid arthritis, etc. It can be used to remove drugs, toxins, cholesterol and other substances, or inflammatory cells such as white blood cells or platelets, which are considered to be the cause of these diseases, from the blood of patients.

As the plasma clearance therapy, a primary membrane is used to separate plasma from the blood, and then the plasma is passed through a dual membrane double membrane filtration plasma exchange therapy (DFPP: Double Filtration Plasmapheresis), or a patient's body fluid is directly processed. Direct HemoPerfusion (DHP). DHP is rapidly gaining popularity in recent years because of its ease of handling. As the use form of the DHP column, in addition to the form of using the column alone, it can also be used in series with an artificial kidney in dialysis for renal failure patients and the like, and it can also be efficiently used. adsorption become beta] as a cause of dialysis complication of dialysis-related amyloid degeneration of the substance of ₂ - microglobulin (β ₂ -Microglobulin) and the like.

In the DHP described above, blood is passed through a column in which an adsorbent is housed inside, and the adsorbent is used to adsorb and remove substances to be removed from the blood. The tubular column usually has a hollow cylindrical sleeve, and a header cap with a blood inlet and an outlet is arranged at both ends in the length direction, and an adsorbent is contained inside the sleeve. . The absorbent body can be held in the cannula by arranging a filter with more fine openings at the blood inflow end and the outflow end of the cannula.

In addition, when a blood purification tube string is used as a medical device by DHP or the like, a so-called priming operation is generally performed before use, that is, physiological saline or the like is fluidized and filled. At this time, if air is generated in the pipe string or circuit and remains in the pipe string, it will hinder the permeation and filling of physiological saline, etc., and the contact area between the adsorbent and the blood will be reduced, resulting in the blood purification pipe string. Cases of reduced adsorption and removal performance. In addition, when the filter sheet arranged at the end of the pipe string is poor in gas evasion, that is, when air enters the pipe string temporarily, the air cannot easily escape to the filter chip outside the pipe string because it remains in the pipe. The air in the column activates the blood in the column, which easily causes blood clotting. Especially when the column is used in the form of in-line connection with the artificial kidney as described above, from the viewpoint of operability, it is preferable that the column and the artificial kidney are washed (priming water injection) before treatment. It is performed in a state where the pipe string and the artificial kidney are connected in series. However, when an artificial kidney in a dry state or a wet state which is not filled with water is used as the artificial kidney, a large amount of air flows into the pipe string. Therefore, as a filter sheet for a column, it is required to be excellent in gas-exhausting property and excellent in biocompatibility, that is, it is difficult to cause blood coagulation and the like in the circuit when blood circulates. Previously, there were patents in which a screen is used for fixing the end of a pipe string used for DHP (Patent Documents 1 and 2). However, as a rule regarding the screen, only a designer who should use an adsorbent to hold the inside of the pipe string is described, and there is no description of the case where the above-mentioned outgassing property is improved by designing the screen. In addition, it is also used to contain hollow fiber or solid fibers. An invention in which the adsorbent having the shape of a column as an adsorbent in the column is provided with a screen at both ends (Patent Document 3). However, there is no opinion on the outgassing in the invention. On the contrary, for the purpose of stably maintaining the adsorption body in the column or improving the fluidity in the column, the mesh-like cloth is rolled into the adsorption body to make it. From the viewpoint of gas evasion, it is not good to arrange such screens with openings in parallel along the long axis direction of the column.

[Prior technical literature] [Non-patent literature]

Non-Patent Document 1: "Chemical Engineering and Artificial Organs 2nd Edition", published by Kyoritsu, 1997, p162 ~ 163

[Patent Literature]

Patent Document 1: Japanese Patent Laid-Open No. 59-95051

Patent Document 2: Japanese Patent Laid-Open No. 2009-254695

Patent Document 3: Japanese Patent Laid-Open No. 2010-148851

The purpose of the present invention is to prevent the activation of blood caused by the air remaining in the column, or to prevent the activation of blood caused by the air remaining in the column, by using the filter sheet contained in the blood purification tube string to greatly improve the outgassing property. The decrease in the contact area between the adsorbent and the blood reduces the adsorption performance.

The blood purification tube column of the present invention is as follows: a sleeve having an adsorbent body and two ends with open ends, the adsorbent body is housed inside the sleeve, and one end of the sleeve is blood The other end is the end of the liquid inflow side, and the other end is the end of the blood outflow side. A filter is arranged at the end of the blood inflow and / or the end of the blood outflow side, and the filter meets the following requirements.

(1) Opening ratio is 5% or more and 80% or less

(2) The equivalent diameter of the mesh is 1 μm or more and 5000 μm or less

(3) The ratio of the equivalent diameter of the mesh to the average circular equivalent diameter of the voids of the adsorbent is 45% or more

Regarding the above (3), there are voids in the contained adsorption system, but in the present invention, it is found that the equivalent diameter of the mesh of the filter sheet is closely related to the average equivalent diameter of the voids of the adsorbent, and By optimizing the ratio between the two, the outgassing property is improved.

In addition, as a filter, its hydrophilicity is important, that is, a material having a contact angle within a suitable range is preferred. Therefore, as the material of the filter sheet, it is preferable to include at least one material selected from the group consisting of polyolefin resin, polyamide resin, and fluorine resin, and it is more preferable to include a material selected from polypropylene, polyethylene, nylon 6, Nylon 66 and its derivatives are at least one kind of material, and more preferably one containing polypropylene or its derivative.

According to the present invention, it is possible to provide a blood purification tube string which can efficiently remove air generated during a water injection operation or the like performed before use to the outside of the tube string, so that blood coagulation in the circuit during blood circulation is difficult to occur.

1‧‧‧ header cap

2‧‧‧ Outlet of treated liquid

3‧‧‧ liquid inlet

4‧‧‧ exit side filter

5‧‧‧Inlet side filter

6‧‧‧ casing

7‧‧‧ adsorbent

8‧‧‧ blood purification tube

9‧‧‧Air injection syringe

10‧‧‧ Pump

11‧‧‧ beaker

12‧‧‧ pure water

13‧‧‧Single-sided installation screen

14‧‧‧ hot bath (37 ℃)

15‧‧‧ Disposable beakers

16‧‧‧Circulation plasma

17‧‧‧Plasma for measuring clearance

Figure 1 is a diagram of a column with an adsorbent embedded therein.

Figure 2 is a diagram of a pipe string with a screen installed on one side.

Fig. 3 is a circuit diagram for measuring the air removal rate in a pipe string having an adsorbent therein.

Fig. 4 is a circuit diagram for measuring the air removal rate in a pipe string with a screen installed on one side.

Fig. 5 is a circuit diagram for measuring β ₂ -MG clearance of a blood purification tube string.

The blood purification pipe string of the present invention includes an adsorbent filled in the pipe string and a filter for holding the adsorbent, and the opening ratio of the filter is 5% or more and 80% or less.

Here, the method of measuring the aperture ratio of the filter is based on the direction of blood flow through the filter when the filter is placed in the column using an optical microscope, that is, there are blood inlets at both ends of the column Observe the same direction from the inlet to the outlet in the case of the outflow. Observe the range surrounded by 5mm square arbitrarily. If the area occupied by the structure constituting the filter in this range is set to A mm ² , The aperture ratio can be expressed by the following formula.

Opening rate (%) = (25-A) / 25 × 100

Regarding one of the target filters, a 5 mm square range was selected at arbitrary five places to measure the aperture ratio, and the average value was obtained. The calculated aperture ratio is rounded off to the first decimal place.

When the aperture ratio is too high, the strength of the filter is insufficient, and it becomes difficult to stably hold the adsorbent body in the sleeve. On the other hand, if the aperture ratio is too low, the resistance to flow increases, and the outgassing property deteriorates. In addition, it becomes easy to cause an increase in pressure loss when blood in the column passes, or an increase in the column pressure when a clot is formed in the filter. According to the above, the upper limit of the aperture ratio is 80% or less, preferably 70% or less, and more preferably 66% or less. On the other hand, the lower limit is 5% or more, preferably 16% or more, and more preferably 21% or more.

The equivalent diameter of the mesh of the filter is an important factor. The measuring method of the equivalent diameter of a mesh is as follows. That is, when the mesh of the filter is uniform in the thickness direction, use an optical microscope to observe the filter from the thickness direction of the filter, and when the mesh of the filter is not uniform in the thickness direction, use a cutter, etc. The mesh was cut to a minimum thickness, and similarly observed from the vertical direction with an optical microscope. 30 voids of the filter were arbitrarily selected, and the respective areas S were measured. The meshes of the respective meshes were calculated by the following formula. Equivalent diameter. Thereafter, an average value of the measured values at 30 points was calculated, and the first digit after the decimal point was rounded.

Equivalent diameter of mesh = 2 × (S / π) ^1/2

If the equivalent diameter of the mesh is too large, it becomes difficult to hold the adsorbent in the column. In addition, if foreign matter is generated in a circuit or a pipe string, the possibility that the filter cannot be used for capturing is also increased. Therefore, specifically, the equivalent diameter of the mesh is preferably 10 times or less, more preferably 5 times or less, and even more preferably 2.8 times the cross-sectional area of each adsorbent when the column is viewed from the longitudinal direction. Times below. Here, the cross-sectional area of each adsorbent is, for example, if it is a solid fiber, the cross-sectional area of each fiber cross-section. If it is a spherical bead, it means that each bead passes through the bead. The area of the surface obtained when the straight line at the center is cut. On the other hand, if the equivalent diameter of the mesh of the filter is too small, the resistance to flow increases and the outgassing property becomes poor. In addition, it becomes easy to cause an increase in pressure loss when blood in the column passes, or an increase in the column pressure when a clot is formed in the filter. According to the above, the upper limit of the equivalent diameter of the mesh is 5,000 μm or less, preferably 800 μm or less, and more preferably 400 μm or less. The lower limit of the equivalent diameter of the mesh is 1 μm or more, preferably 5 μm or more, and more preferably 10 μm or more.

The outgassing property can be evaluated by the following method. Filter plates and collecting headers with the inlet and outlet of the liquid to be treated are arranged at both ends of the blood purification tube string After the inside of the column was washed with pure water, the ports were sealed with the cover. This pipe string was installed in the circuit for the gas escape test as shown in Fig. 2 with its length direction perpendicular to the ground. The removal rate of air in the pipe string trapped by the screen was measured 5 times by the following procedure, and The first digit after the decimal point is rounded to find the average value of the air removal rate.

(1) Use a pump to circulate pure water at a flow rate of 100 ml / s until the air in the circuit completely escapes. If necessary, tap the pipe string to completely expel the air.

(2) Stop the pump, while taking care not to mix air, remove the pipe string from the circuit, and cover the inlet and outlet of the liquid to be treated respectively. The column weight at this time was measured and set to A.

(3) The column after the weight measurement is put back into the circuit again, and the pure water is circulated at a flow rate of 100 ml / s.

(4) From the inlet of the liquid to be treated of the column to the upstream of the circuit 1 cm, use a syringe to inject 10 ml of dry air for 5 seconds.

(5) Circulate pure water directly at a flow rate of 100 ml / s for 1 minute. During this period, the circuit is in a static state.

(6) Stop the pump, while taking care not to mix air, remove the pipe string from the circuit, and cover the inlet and outlet of the liquid to be treated respectively. The column weight at this time was measured, and it was set to B.

(7) Calculate the removal rate of air in the column according to the following formula.

Air removal rate in the column (%) = (A-B) / A × 100. The air removal rate is preferably 43% or more, more preferably 55% or more, and even more preferably 63% or more.

The so-called adsorbent in the present invention is the same as the adsorbent in the above-mentioned medical equipment, and is a substance that adsorbs and removes a substance to be removed from the blood. The form of the adsorbent to be filled can be flat film, powder, spherical particles, broken particles, massive continuous bodies, fibrous, tubular, hollow fiber, solid fiber, granular, plate, broken Hollow fibrous, Any shape such as a broken solid fibrous shape. Among them, if it is a linear, tubular, hollow fiber, or solid fiber shape arranged in parallel along the length of the column, the flow path will also be a straight line. The length of the flow path can be set to a minimum, so air is not easily trapped, so Better. Furthermore, in the case of hollow fibrous or solid fibrous, the adsorption area can be sufficiently ensured by making the thickness of the membrane or the inside of the fiber porous, which is suitable for adsorption, so that the content contained in blood can be efficiently contained. The target substance is adsorbed and removed. Compared with ultrafine fibers, broken hollow fibers, broken solid fibers, etc., there is a higher viscosity of the treated liquid, such as the patient's whole blood, and a higher risk of coagulation in the column. The advantage can also be used in high situations. Further, it is particularly preferable that the fibers are solid and fibrous. The reason is that in the case of hollow fibers, there are cases where the pressure loss between the inside and outside of the hollow fiber is different, etc., the flow rate of the liquid to be treated varies between the inside and outside of the hollow fiber, and as a result, the adsorption efficiency of the column may be reduced. In addition, in order to make the pressure loss on the inside and the outside of the hollow fiber equal, the inner diameter of the hollow fiber and the filling rate of the pipe string are greatly restricted. Furthermore, when a tubular string filled with hollow fibers flows through the blood, compared with the environment outside the hollow fibers in the tubular string, the hollow portions of the hollow fibers are fixed in a closed environment, and there is a concern that blood clots are likely to be formed. . Furthermore, the gaps outside the hollow fibers are deformed due to the movement of the fibers in the pipe string, so they are not a fixed closed environment. Here, the above-mentioned linear shape arranged in parallel along the length of the pipe string refers to a shape in which the end faces on both sides of a fiber contact the inlet and outlet end faces of the pipe string as close as possible to the shortest distance. Among them, the fibers may be crimped, such as crimps. Moreover, it is preferable that the porous adsorbent has a porous structure that is homogeneous in the thickness direction. Thereby, the area contributing to adsorption can be increased. On the other hand, when the pore structure is an asymmetric structure with a gradient or an irregular structure in the thickness direction, the specific surface area of the adsorbent decreases, which is unfavorable.

When the fiber is crimped, such as crimping, in order to obtain the filling rate described below, the fiber length is measured in a state of a linear shape where both ends of the fiber are elongated, and it is used as a pipe string. The measuring method of the length of the linear fiber contained in the length direction is to fix one end of the fiber extracted from the column with tape, and give a weight of about 3g to the other end to quickly measure the total length of the fiber when it becomes linear. . This measurement was performed on arbitrary 30 fibers in the column, and the average value of 30 fibers was calculated.

In the present invention, the ratio of the equivalent diameter of the mesh of the filter to the average circular equivalent diameter of the voids of the adsorbent is 45% or more, preferably 50% or more, and more preferably 56% or more. The above ratio is preferably 400% or less, more preferably 280% or less, and still more preferably 220% or less. Here, the above-mentioned average circular equivalent diameter De is as described in Non-Patent Document 1 when the adsorbent has a linear shape arranged parallel to the length of the column such as a tube, a hollow fiber, or a solid fiber, etc. It is represented by the following formula.

Average circular equivalent diameter of the gap of the adsorbent De = 4 × Af / Wp

Af in the formula is the cross-sectional area of the flow path, and is a value obtained by subtracting the sum of the cross-sectional area of the cross-section in the direction perpendicular to the length direction of the sleeve and the cross-sectional area of the cross-section in the same direction occupied by the adsorbent. The total of the cross-sectional area occupied by this adsorbent can be determined from the fiber diameter D0 obtained by the following fiber diameter measurement method and the number N of filled fibers in the column, and can be determined by the following formula.

Sum of the cross-sectional area occupied by the adsorbent = (D0 / 2) ² × π × N

Wp is the length of the wet side, and is the sum of the inner surface area of the sleeve and the total surface area of the adsorbent. The total surface area of the adsorbent can be determined by the following formula from the fiber diameter D0, the number N of the filled fibers in the column, and the length L of the fibers in the length direction.

Total surface area of the adsorbent = D0 × π × L

The shape of the sleeve is an open end at both ends. For example, a rectangular cylinder or a cylindrical cylinder such as a quadrangular cylinder or a hexagonal cylinder can be mentioned. Among them, a cylindrical body is preferred, and a cylindrical body having a perfect circular cross section is particularly preferred. . The reason is that blood can be prevented from staying in the corner by making the cannula no corner. also, By setting the two sides as open ends, blood flow is less likely to become turbulent and pressure loss is minimized. The sleeve is preferably a device including plastic or metal. In the case of plastic, for example, a thermoplastic resin having excellent mechanical strength and thermal stability can be used. Specific examples of such thermoplastic resins include polycarbonate resins, polyvinyl alcohol resins, cellulose resins, polyester resins, polyarylate resins, polyimide resins, and cyclic resins. Polyolefin resin, polyfluorene resin, polyether resin, polyolefin resin, polystyrene resin, polyvinyl alcohol resin, and mixtures thereof. Among these, in terms of formability, transparency, and radiation resistance required for the sleeve, polystyrene, polycarbonate, and derivatives thereof are preferred. This is because a resin with excellent transparency can confirm the internal condition during blood perfusion, so it is convenient to ensure safety, and a resin with excellent radiation resistance is better for radioactive irradiation during sterilization. In the former case, an appliance is produced by injection molding using a mold or by cutting the material, and in the latter case, an appliance is produced by cutting the material. Among these, plastic is preferably used from the viewpoints of cost, formability, weight, and blood compatibility.

When the adsorbent is in a shape that is not linear with respect to the direction of blood flow in the column such as particles, powder, or broken lines, the average circular equivalent diameter De can be determined by the following formula.

Average circular equivalent diameter of the gap of the adsorbent De = (32 × μ × L × u / △ P) ^1/2

In the formula, μ is the viscosity of the liquid to be treated, L is the length in the length of the adsorbent filling part, u is the average flow velocity in the column, and △ P is the pressure loss from the inlet of the column minus the pressure at the outlet of the column. The value gained through loss.

In the case where the ratio of the equivalent diameter of the mesh of the filter to the average circular equivalent diameter of the voids of the adsorbent is less than 45%, the mesh of the filter is significantly smaller than the cross-sectional area of the air passing through the column. Therefore, it is difficult to pass the filter and the air is easy The tendency to stay in the column. On the other hand, when the ratio of the equivalent diameter of the mesh of the filter to the average circular equivalent diameter of the voids of the adsorbent is more than 400%, the adsorbent becomes easy to flow out of the filter mesh, and it is difficult to keep it in the tube. The condition of the adsorbent in the column. The calculated equivalent diameter of the mesh is obtained by rounding off the first digit after the decimal point, and then calculating the above ratio.

In addition, when the hollow fiber or solid fiber is filled as an adsorbent, if the fiber diameter (the outer diameter of the fiber in the case of a hollow fiber) is too small, the pressure loss of the pipe string increases, or the fiber itself passes through. Dangers of filters. On the other hand, when it is too large, the contact area between the adsorbent and blood is reduced, and the efficiency of blood purification is deteriorated. Therefore, the fiber diameter is preferably 1,000 μm or less, more preferably 450 μm or less, and even more preferably 280 μm or less. As a lower limit, 5 μm or more, more preferably 30 μm or more, and even more preferably 70 μm or more.

As for the measurement method of the fiber diameter, 50 fibers are randomly selected from the fibers filled in the column, and after washing these fibers, they are completely replaced with pure water, sandwiched between a slide glass and a cover glass, and used. For a projector (such as the V-10A manufactured by Nikon), the outer diameter (outer diameter) of each of the two fibers is arbitrarily measured for the same fiber, the average value is used, and the first digit after the decimal point is rounded. . When the number of filled hollow fibers is less than 50, all fibers are measured, and the average value is similarly used.

From the viewpoint of preventing the adsorbent from flowing out of the bloodstream, the mesh of the filter is preferably set to such an extent that blood passes through but the adsorbent does not pass. That is, the mesh is preferably set to a diameter of each of the adsorbed bodies to be filled.

As the material of the filter sheet, metal materials such as aluminum, natural materials such as silk, and polymer compounds can be used alone or in combination. Among them, in terms of cost or strength, weight, From the viewpoint of physical compatibility and the like, a polymer compound can be preferably used, and it is particularly preferable to include at least one material selected from a polyolefin resin, a polyamide resin, and a fluorine resin. The reason can be cited as: the control of the hydrophilicity and hydrophobicity is required for the filter of the blood purification column. That is, if a material having a high contact angle between the filter material and water is used, the outgassing ability flowing into the pipe string can be improved. If the contact angle between the filter and water is too low, the outgassing property is deteriorated and air tends to remain in the pipe string. On the other hand, when it is too high, non-specific adsorption of proteins and the like to the filter is caused, which leads to platelet adhesion and the like, thereby causing blood coagulation and the like. Therefore, the upper limit of the contact angle is preferably 125 ° or less, more preferably 108 ° or less, and even more preferably 104 ° or less. On the other hand, as the lower limit, it is preferably 66 ° or more, and more preferably 72 ° or more. Particularly preferred is 82 ° or more.

Here, the contact angle of a structure such as a filter is affected by the fiber diameter and fiber density. Therefore, the contact angle between the filter material and water refers to measuring the surface of the film after making a uniform film containing the same material as the filter. The angle of the inside of the liquid obtained from the angle to the surface of the liquid. Specifically, a solution is prepared by dissolving a filter in a good solvent, the solution is flowed into an aluminum pan, and the good solvent is evaporated and solidified in a dry environment to produce a thin film.

The measurement of the contact angle can be performed at room temperature (23 ° C.) using a contact angle meter (for example, Kyowa Interface Science Co., Ltd., DropMaster DM500). In the calculation, the droplet method can be used, and a 2 μL droplet is made using a syringe and brought into contact with the substrate. The tangent line of the droplet drawn from the contact surface of the substrate, the droplet, and the three phases of the gas phase is obtained. Angle with the droplet-substrate interface. In addition, each measurement value measured the contact angle with the base material at 10 places, and calculated | required the average value. The calculated contact angle is rounded off to the first decimal place.

Here, regarding the case where the outgassing property is improved due to the increase in contact angle, The explanation is based on the decrease in the interfacial tension between solids and air. That is, when water contacts the surface of a solid, the interfacial tension between solid and air is set to γ1, the interfacial tension between water and solids is set to γ2, the interfacial tension between water and air is set to γ3, and the tangent to the air-liquid interface When the angle formed by the direction and the direction of the solid-liquid interface is θ, the force balance is expressed by the following formula.

γ1 = γ3 × cosθ + γ2

Here, the θ-based contact angle can decrease γ1 by increasing the contact angle.

Examples of the polymer compound having a contact angle of 66 ° or more and 125 ° or less include (meth) acrylic resins, olefin resins, polysiloxane resins, polyvinyl chloride resins, and polyvinylidene chloride. Vinyl resin, fluorine resin, polyester resin, or a mixture thereof. Among them, polyolefin-based resins, polyamide-based resins, and fluorine-based resins can be preferably used from the viewpoints of production cost, ease of molding, and durability to sterilization, and polypropylene is more preferable. , Polyethylene, nylon 6, nylon 66 and their derivatives. Especially preferred are polypropylene and its derivatives.

The form of the filter sheet may be any of a porous body and a porous body, and a porous body with pores evenly spaced may be preferably used, and examples thereof include a screen and a nonwoven fabric. Among them, a sieve can be preferably used in terms of less adherence of blood cell components due to uniform meshes, and less occurrence of leachables from the filter sheet.

Furthermore, in order to prevent deterioration of the outgassing property of the filter sheet, it is preferable that the entire filter sheet has a uniform opening portion. Here, the so-called filter sheet has uniform openings throughout, and refers to a filter sheet in which, when the aperture ratio is not fixed, even if any arbitrary 5 mm square range is selected throughout the entire filter sheet, the variation range of the aperture ratio value It is also included within ± 30% of the average value, more preferably ± 18% or less, and even more preferably ± 10% or less.

If the thickness of the filter sheet is too thick, it will cause adsorption in the column The filling rate of the body is reduced, so the blood purification efficiency is reduced. In addition, the pressure loss during the passage of blood in the column also increases. On the other hand, if the thickness of the filter sheet becomes too thin, the strength of the filter sheet becomes insufficient, and it becomes difficult to stably hold the adsorbent body on the sleeve. According to the above, the upper limit of the thickness of the filter is preferably 3000 μm or less, and more preferably 900 μm or less. The lower limit of the thickness of the filter is preferably 0.1 μm or more, and more preferably 40 μm or more.

Further, regarding the filter piece held in the column, the surface area of the portion which is open in a direction perpendicular to the long axis direction in the column is set to B1, and the surface area of the filter piece is set to be perpendicular to the long axis direction in the column. In the case where the total surface area of the portion that is open outside the direction is set to B2, it is preferable to reduce the area of B2 as much as possible. The reason may be considered to be used for the purpose of stably holding the adsorbent in the column with a filter sheet, or to improve the fluidity in the column with the filter sheet as a spacer, etc. Filters with openings other than the direction perpendicular to the long axis, but such screens are likely to hinder the flow of air flowing through the gap of the adsorbent, and it is easy to trap air, which is not good. In addition, there is a possibility that the amount of the adsorbable body that can be filled in the pipe string is reduced, resulting in a decrease in the adsorption performance. Specifically, it is preferable to satisfy the relationship of B1 / B2 ≧ 1.0, more preferably B1 / B2 ≧ 5.0, and even more preferably B1 / B2 ≧ 10.0. In addition, when the opening is not perpendicular or parallel to the long axis direction in the column but is inclined in the oblique direction, it is assumed that it is not included in any of the above denominator and numerator.

As a form of a column equipped with a filter sheet, it usually includes: a sleeve provided with an inlet portion where blood flow before purification and an outlet portion where blood flow is discharged after purification; an adsorbent housed in the sleeve; A filter sheet inside the inlet and / or outlet; and a header cover provided with blood inlets and outlets arranged at both ends in the length direction of the cannula. The filter sheet is preferably arranged on both sides of the inlet and the outlet in a manner that the adsorbent is held in the sleeve, and when the adsorbent can be held on only one side of the inlet and the outlet, It can be used alone, or the filter sheet of the present invention can be arranged on one side of the column, and the filter sheet different from the present invention can be arranged on the opposite side.

The upper limit of the filling rate of the adsorbent in the sleeve of the pipe string is preferably less than 70%, and more preferably 63% or less. The lower limit of the filling rate of the adsorbent is preferably 13% or more, more preferably 30% or more, and even more preferably 45% or more. By setting the filling rate of the adsorbent to 13% or more, the amount of blood necessary for blood purification is reduced, and thus the burden on the patient can be reduced. On the other hand, when the filling rate of the adsorbed body is 70% or more, the outgassing property is deteriorated. In addition, since it becomes difficult to fill the adsorbent, work efficiency is reduced. In addition, the filling rate here refers to the ratio of the volume of the adsorbent to the volume of the cannula provided with the inlet portion in which the blood flow before the purification is provided and the outlet portion where the blood flow is discharged after the purification, and does not include the above. Collecting department, etc.

Regarding an example of producing the blood purification tube string of the present invention, an example in which a fiber shape is used as a solid fiber is shown below, but the present invention is not limited to this.

A spinning dope prepared by dissolving a polymer in a solvent is prepared. The spinning dope is discharged from a nozzle having a round dope outlet and is coagulated into a solid fiber shape by a coagulation bath. The coagulation bath usually contains a coagulant such as water or alcohol, or a mixture with a solvent constituting the spinning dope. In addition, the porosity can be changed by controlling the temperature of the coagulation bath. The porosity can be affected by the type of spinning dope, etc., so the temperature of the coagulation bath is also an appropriate choice, but usually the porosity can be increased by increasing the temperature of the coagulation bath. The mechanism is not clear, but it may be considered that the reason may be that in the competitive reaction between desolvation from the original solution and coagulation and shrinkage, the desolvation is faster in a high-temperature bath, so that it is solidified and fixed before shrinking. However, if the temperature of the coagulation bath becomes too high, the pore diameter becomes too large. Therefore, for example, solid fibers are fibers containing polymethyl methacrylate (hereinafter referred to as PMMA), and solidification in the case where gas is added to the inner tube. The bath temperature is preferably 39 ° C or higher, and more preferably 42 ° C or higher. On the other hand, better The temperature is 50 ° C or lower, more preferably 46 ° C or lower.

Next, a step of washing the solvent adhered to the solidified solid fibers is performed. The method of washing the solid fibers is not particularly limited, and a method may be preferably used in which the solid fibers are passed through a multi-stage bath filled with water (referred to as a water bath). The temperature of the water in the water bath may be determined according to the properties of the polymer constituting the fiber. For example, in the case of PMMA-containing fibers, 30 to 50 ° C can be used.

In addition, in order to maintain the pore diameter of the solid fiber after bathing in water, a step of imparting a moisturizing component to the solid fiber may be added. The moisturizing component herein refers to a component that can maintain the humidity of solid fibers or a component that prevents the humidity of solid fibers from decreasing in the air. Typical examples of moisturizing ingredients include glycerin or an aqueous solution thereof.

After the washing or the moisturizing ingredient is given, in order to improve the dimensional stability of solid fibers with high shrinkage, a bath filled with an aqueous solution of the heated moisturizing ingredient (called a heat treatment bath) may be used. The heat treatment bath is filled with an aqueous solution of the heated moisturizing ingredient, and the solid fibers are passed through the heat treatment bath, thereby being contracted by the effect of heat, so that it becomes difficult to shrink in the subsequent steps, and the fiber structure can be stabilized. The heat treatment temperature at this time varies depending on the fiber material. In the case of PMMA-containing fibers, the temperature is preferably 75 ° C or higher, and more preferably 82 ° C or higher. The temperature is preferably 90 ° C or lower, and more preferably 86 ° C or lower.

An example of a method for purifying a pipe string using the obtained solid fiber is as follows.

First, the solid fiber is cut to a necessary length, the necessary number is bundled, and then it is put into a plastic sleeve which becomes the barrel portion of the blood purification tube string. Thereafter, the two ends of the solid fiber are cut by means of a cutter or the like so that the solid fiber is received in the casing, and the outflow inlets of the treated liquid at the two end surfaces of the both ends of the column are installed as shown in Figure 1. Like, cut Cut into a mesh filter with the same diameter as the inner diameter. Finally, the inlet and outlet ports of the liquid to be treated, which is called a header head cover, are installed to obtain a blood purification tube string.

Moreover, when it is used for a medical appliance etc., it is preferable to use for sterilization or sterilization. Examples of the sterilization and sterilization methods include various sterilization and sterilization methods such as high-pressure steam sterilization, γ-ray sterilization, ethylene oxide gas sterilization, pharmaceutical sterilization, and ultraviolet sterilization. Among these methods, γ-ray sterilization, high-pressure steam sterilization, and ethylene oxide gas sterilization have less influence on sterilization efficiency and materials, and are therefore preferred.

As the use form of the blood purification tube string in the present invention, from the viewpoints of a single treatment amount and ease of operation, a method is preferred in which it is mounted on an extracorporeal circulation circuit and is adsorbed and removed on-line. In this case, the purification column of the present invention may be used alone, or it may be used in parallel with an artificial kidney or the like during dialysis.

[Example] [Example 1]

31.7 parts by weight of syn-PMMA with a weight average molecular weight of 400,000, 31.7 parts by weight of syn-PMMA with a weight average molecular weight of 1.4 million, 16.7 parts by weight of iso-PMMA with a weight average molecular weight of 500,000, and containing sodium p-styrene sulfonate 20 parts by weight of 1.5 mol% PMMA copolymer having a molecular weight of 300,000 was mixed with 376 parts by weight of dimethyl sulfene, and stirred at 110 ° C. for 8 hours to prepare a spinning dope. The obtained spinning dope had a viscosity of 1240 poise at 110 ° C. The obtained spinning dope was discharged into the air at a speed of 1.0 g / min from a nozzle having a circular discharge port having a diameter of 0.3 mm kept at 93 ° C, and after traveling 50 cm in the air, it was guided to a coagulation bath. A solid fiber was obtained by setting the water temperature (coagulation bath temperature) used in the coagulation bath to 42 ° C. After each solid fiber was washed with water, glycerin was added as a moisturizing agent in the form of a 70% by weight aqueous solution, and then the temperature of the heat treatment bath was set to 84 ° C. After the oil was removed, the spacer fibers were wound and wound up at 42 m / min. The fiber diameter of the obtained solid fiber was measured using a projector V-10A manufactured by Nikon Corporation, and it was 121 μm.

The obtained solid fibers were bundled by a known method, and a solid fiber having a diameter of 121 μm was embedded in a polycarbonate cylindrical sleeve having an inner diameter of 38 mm and an axial length of 133 mm so that the filling ratio became 57%. . Second, install the outflow inlets of the liquid to be treated on both sides of the tubing string as shown in Figure 1. Polypropylene made of a mesh equivalent diameter of 84 μm and an opening ratio of 36% cut to the same diameter as the inner diameter of the sleeve Screen filter. In addition, the equivalent diameter of the mesh of the filter, the aperture ratio, and the filling rate of the column were measured using a projector V-10A manufactured by Nikon Corporation, and calculated by various methods described above.

Furthermore, a header head cap provided with an inlet and an outlet of the liquid to be treated is arranged at both ends of the column, and then the inside of the column is washed with pure water, and then each port is sealed with the cap, and screens are installed on both sides. The column of the net. The average circular equivalent diameter of the adsorbent voids of this column was 91 μm. This pipe string was installed in the circuit for the gas escape test as shown in Fig. 2 with its length direction perpendicular to the ground, and the removal rate of air in the pipe string trapped by the screen was measured by the following procedure.

(1) Use a pump to circulate pure water at a flow rate of 100 ml / s until the air in the circuit completely escapes. If necessary, an impact is applied to the pipe string, and the air is easily expelled.

(2) Stop the pump, while taking care not to mix air, remove the pipe string from the circuit, and cover the inlet and outlet of the liquid to be treated respectively. The column weight at this time was measured and set to A.

(3) The column after the weight measurement is put back into the circuit again, and the pure water is circulated at a flow rate of 100 ml / s.

(4) From the inlet of the liquid to be treated of the column to the upstream of the circuit 1 cm, use a syringe to inject 10 ml of dry air for 5 seconds.

(5) Circulate pure water directly at a flow rate of 100 ml / s for 1 minute. During this period, the circuit is in a static state.

(6) Stop the pump, while taking care not to mix air, remove the pipe string from the circuit, and cover the inlet and outlet of the liquid to be treated respectively. The column weight at this time was measured, and it was set to B.

(7) Calculate the air removal rate in the column according to the following formula. The results are shown in Table 1.

Air removal rate in the column (%) = (A-B) / A × 100.

[Example 2]

A solid fiber was obtained by the same method as in Example 1 except that the spinning speed of the spinning dope was set to 1.9 g / min, thereby setting the fiber diameter to 181 μm. In the sleeve, solid fibers obtained in the same manner as in Example 1 were built-in, and the same size and shape of screen filters and header caps as in Example 1 were arranged on the end faces on both sides of the sleeve. The average circular equivalent diameter of the adsorbent voids of this column was 135 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1.

[Example 3]

Except that the spinning speed of the spinning dope was set to 0.5 g / min, thereby setting the fiber diameter to 56 μm, a solid fiber was obtained by the same method as in Example 1. In the sleeve, solid fibers obtained in the same manner as in Example 1 were built-in, and the same size and shape of screen filters and header caps as in Example 1 were arranged on the end faces on both sides of the sleeve. The average circle diameter of the adsorbent voids of the column The gauge diameter is 42 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1.

[Example 4]

The solid fibers were obtained by the same method as in Example 1. The solid fibers obtained in the same size and shape as in Example 1 were embedded in the same way as in Example 1. In the same manner as in Example 1, a polypropylene mesh filter with a mesh equivalent diameter of 124 μm and an opening ratio of 31%, and a header cap of the same size and shape as in Example 1 were arranged. The average circular equivalent diameter of the adsorbent voids of this column was 91 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1. In addition, in order to evaluate the protein removal performance of the obtained purification column, β ₂ -MG (microglobulin) clearance was measured by the method shown below. The results are shown in Table 3.

Method for measuring β ₂ -MG clearance

As a performance evaluation of the adsorption column, the clearance of β ₂ -MG was measured. Β ₂ -MG is known as a cause protein of dialysis-related amyloidosis due to long-term dialysis complications.

For cow blood to which disodium ethylenediamine tetraacetate was added, the blood volume ratio was adjusted to 30 ± 3%, and the total protein mass was adjusted to 6.5 ± 0.5g / dL. Use cattle blood within 5 days after blood collection.

Next, the β ₂ -MG concentration was added and stirred so that the concentration became 1 mg / l. The bovine blood was classified as follows, that is, 2 L was used for circulation, and 1.5 L was used for measurement of clearance.

The circuit is set up as shown in Figure 5. In the circuit, the liquid inlet portion that takes in the liquid to be treated is set to Bi, and the liquid outlet portion after the blood purification tube string is passed through the liquid is set to Bo.

Put Bi into a circulation beaker containing 2L of beef blood (37 ° C) adjusted above, set the flow rate to 200 mL / min, start the pump, and discard 90 seconds of the liquid discharged from Bo. Immediately Bo was put into a circulation beaker and set to a circulation state.

Stop the pump after 1 hour of cycling.

Next, Bi was placed in the bovine blood for the above-mentioned adjusted clearance measurement, and Bo was placed in a beaker for disposal.

The flow rate was set to 200 mL / min, and 2 minutes after the pump was started, 10 ml of a sample was taken from the bovine blood (37 ° C.) for measuring the clearance, and the solution was set to Bi. After 4 minutes and 30 seconds elapsed after starting, 10 ml of a sample flowing from Bo was taken as the Bo solution. These samples are stored in a freezer below -20 ° C.

The clearance was calculated from the β ₂ -MG concentration of each solution by the following formula I. Since the measured value may vary depending on the lot of bovine blood, the same lot of bovine blood is used in the examples and comparative examples.

Co (ml / min) = (CBi-CBo) × Q _B / CBi (I)

In formula I, C _o = β ₂ -MG clearance (ml / min), CBi = 2 -MG concentration of Bi liquid β, CB _o = ₂ -MG concentration Bo solution of β, Q _B = Bi pump flow (ml / min).

[Example 5]

The solid fibers were obtained by the same method as in Example 1. The solid fibers obtained in the same size and shape as in Example 1 were embedded in the same way as in Example 1. In the same manner as in Example 1, a polyethylene terephthalate screen filter with a mesh equivalent diameter of 108 μm and an opening ratio of 40%, and a header cap of the same size and shape as in Example 1 were arranged. The average circular equivalent diameter of the adsorbent voids of this column was 91 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1. The β ₂ -MG clearance was measured by the same procedure as in Example 4. The results are shown in Table 3.

[Example 6]

A solid fiber was obtained by the same method as in Example 1 except that the spinning speed of the spinning dope was set to 4.7 g / min, thereby setting the fiber diameter to 260 μm. In the sleeve, solid fibers obtained in the same manner as in Example 1 were embedded, and in the same manner as in Example 5, the mesh equivalent diameter of 108 μm and the aperture ratio of 40 were arranged on the both end faces of the sleeve as in Example 1. % Polypropylene mesh filter sheet, and a header cap of the same size and shape as in Example 1. The average circular equivalent diameter of the adsorbent voids of this column was 194 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1. The β ₂ -MG clearance was measured by the same procedure as in Example 4. The results are shown in Table 3.

[Comparative Example 1]

A solid fiber was obtained by the same method as in Example 1 except that the spinning speed of the spinning dope was set to 4.7 g / min, thereby setting the fiber diameter to 260 μm. In the sleeve, solid fibers obtained in the same manner as in Example 1 were built-in, and the same size and shape of screen filters and header caps as in Example 1 were arranged on the end faces on both sides of the sleeve. The average circular equivalent diameter of the adsorbent voids of this column was 194 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1. The β ₂ -MG clearance was measured by the same procedure as in Example 4. The results are shown in Table 3.

[Example 7]

The same spinning dope as in Example 1 was used. The outer diameter / inner diameter of the annular slit portion kept at 93 ° C was 2.1 / 1.95mm. The double-tube hollow fiber nozzle is discharged into the air at a speed of 2.5 g / min. Here, nitrogen is injected into the inner tube portion of the double tube at the same time, and after moving 50 cm in the air, it is led to the coagulation bath. A hollow fiber membrane was obtained by setting the water temperature (coagulation bath temperature) used in the coagulation bath to 42 ° C. Each hollow fiber membrane was washed with water, and glycerin was added as a humectant in the form of a 70% by weight aqueous solution. The heat treatment bath temperature was set to 84 ° C. After removing excess glycerin, the spacer fibers were wound and rolled at 60 m / min take. The fiber diameter of the obtained hollow fiber was measured using a projector V-10A manufactured by Nikon Corporation. As a result, the inner diameter was 200 μm and the fiber outer diameter was 260 μm. The hollow fiber having the same size and shape as in Example 1 was embedded in the same way as in Example 1. The hollow fibers were obtained in the same manner as in Example 6. At the end faces on both sides of the sleeve, the same as in Example 1. A polypropylene mesh filter with a mesh equivalent diameter of 108 μm and an opening ratio of 40%, and a header cap of the same size and shape as in Example 1 were provided. The average circular equivalent diameter of the adsorbent voids of this column was 195 μm. For this pipe string, the same procedure as in Example 1 was used to measure the air removal rate in the pipe string. The results are shown in Table 1.

[Reference Example 1]

At the end face of the treated liquid outflow side of the cylindrical sleeve with an inner diameter of 46 mm and a length of 100 mm in the axial direction, a cylindrical mesh cut into the same diameter as the inner diameter of the outlet of the treated liquid is installed as shown in FIG. 2. Polypropylene mesh filter with an equivalent diameter of 326 μm and an aperture ratio of 51%. Furthermore, a header head having an inlet and an outlet for the liquid to be treated was arranged at both ends, and a column with a screen mounted on one side was produced. Furthermore, no adsorbent is built in. With respect to the single-sidedly installed mesh screen, the same procedure as in Example 1 was used to determine the air removal rate in the string. The results are shown in Table 2.

[Reference Example 2]

On the end face of the treated liquid outflow side of the casing of the same size and shape as in Reference Example 1, a cylindrical mesh with an equivalent diameter of 274 μm and an opening ratio of 45% cut to the same diameter as the inner diameter of the outlet of the treated liquid was installed. With the exception of a PTFE mesh filter with a thickness of 245 mm, a single-sided screen mesh column was fabricated in the same manner as in Reference Example 1. With respect to the single-sidedly installed mesh screen, the same procedure as in Example 1 was used to determine the air removal rate in the string. The results are shown in Table 2.

[Reference Example 3]

On the end face of the treated liquid outflow side of the casing of the same size and shape as in Reference Example 1, a cylindrical mesh with an equivalent diameter of 274 μm and an opening ratio of 37% cut into the same diameter as the inner diameter of the outlet of the treated liquid was installed. With the exception of a 291-mm-thick nylon 66 mesh filter, the same method as in Reference Example 1 was used to make a pipe string with a single-sided screen. With respect to the single-sidedly installed mesh screen, the same procedure as in Example 1 was used to determine the air removal rate in the string. The results are shown in Table 2.

[Reference Example 4]

On the end face of the treated liquid outflow side of the casing of the same size and shape as in Reference Example 1, a cylindrical mesh with an equivalent diameter of 308 μm and an opening ratio of 42% cut into the same diameter as the inner diameter of the outlet of the treated liquid was installed. Except for a polyethylene mesh filter sheet having a thickness of 280 mm, a single-sided screen mesh column was manufactured in the same manner as in Reference Example 1 except for this. With respect to the single-sidedly installed mesh screen, the same procedure as in Example 1 was used to determine the air removal rate in the string. The results are shown in Table 2.

According to the results in Table 1, it can be seen that if the ratio of the equivalent diameter of the mesh to the average circular equivalent diameter of the voids of the adsorbent in the column is more than 45%, the air removal rate in the column can obtain a higher value. 45%, the air removal rate in the column shows a lower value of 59%. It can be considered that the reason is that when the equivalent diameter of the mesh of the filter is smaller than the average circular equivalent diameter of the gap of the adsorbent in the column, the mesh of the filter is significantly smaller than the cross-sectional area of the air passing through the column. Therefore, the air is easily trapped by the filter. Furthermore, compared to polyethylene mesh screens, polypropylene mesh screens show slightly higher air removal rates.

From the results in Table 2, it can be seen that even if a sieve having an opening ratio approximately equal to the mesh equivalent diameter is used, the higher the contact angle, the higher the air removal rate in the column. The reason is considered to be that the interface tension between the solid and air can be reduced by increasing the contact angle.

Based on the results in Table 3, it can be seen that for a pipe string with the same fiber diameter and filling rate of the adsorbent, the relationship between the air removal rate in the pipe string and the β ₂ -MG clearance rate is that the lower the air removal rate in the column, the β ₂ -MG The lower the clearance rate, the lower the adsorption performance of the protein. Moreover, in the results of Table 3, the fiber diameter of the adsorbent of the column of Examples 4 and 5 was 121 μm. On the other hand, the fiber diameter of the adsorbent of the column of Example 6 and Comparative Example 1 was 260 μm. The filling rate of the adsorbent of any column is 57%. Therefore, the surface area of the adsorbent of each column is different in a column with a fiber diameter of 121 μm and a column with a fiber diameter of 260 μm, so it can be considered that this results in protein Difference in adsorption performance.

Claims (5)

A blood purification tube string is characterized in that it has an adsorbent body and a sleeve with open ends at both ends. The adsorbent body is accommodated inside the sleeve, and one end of the two ends of the sleeve is a blood inflow side end. One end is a blood outflow end, and a filter is arranged at the blood inflow side end and / or the blood outflow side end of the above-mentioned cannula, and the following necessary conditions are satisfied: (1) the opening rate of the filter is 5% or more and 80% or less (2) The equivalent diameter of the mesh of the filter is 1 μm or more and 5000 μm or less (3) The ratio of the equivalent diameter of the mesh of the filter to the average circular equivalent diameter of the voids of the adsorbent is 45% or more ( 4) The shape of the adsorbent is solid fibrous. The solid fibrous is arranged in parallel along the length of the column. (5) In the filter, the surface area of the portion that will open in a direction perpendicular to the length in the column is set. For B1, when the total surface area of the portion that is open in a direction parallel to the longitudinal direction in the column is set to B2, the following relationship is satisfied: B1 / B2 ≧ 1 (6) The shape of the filter is mesh. For example, the blood purification tube string of the first patent application range, wherein the filter sheet includes at least one material selected from the group consisting of polyolefin resin, polyamide resin, and fluorine resin. For example, the blood purification tube string of the first or second patent application range, wherein the filling rate of the adsorbent in the storage space in the tube string is 30% or more and less than 70%. For example, the blood purification tube string of the first patent application range, wherein the fiber diameter or outer diameter of the solid fiber is 10 μm or more and 1000 μm or less. For example, the blood purification tube string of the scope of patent application No. 1 or 2 can be used for serial connection with artificial kidneys.